Despite tremendous efforts in research, therapy for stroke is still ineffective. During the last several years, we have made substantial advances in neuroprotection for ischemic stroke by establishing that moderate- to high- dose human albumin administration is a potent neuroprotective therapy in ischemic stroke-a therapy currently in clinical trial. Recently, we have established that human serum albumin (Alb) complexed to the omega-3 fatty acid docosahexaenoic acid (DHA, 22:6n-3) may be equally efficacious or even superior to native albumin as a neuroprotectant, and requires smaller albumin doses to achieve a therapeutic effect. This new, combined agent now requires further validation in fundamental and translational studies. Aim 1, focusing on ischemic stroke, tests the hypothesis that DHA-Alb attenuates brain damage during focal cerebral ischemia. We will use MRI to establish whether DHA-Alb modifies the topography and/or life-span of the ischemic penumbra, to elucidate the dose response and therapeutic window, to document of an enduring effect in chronic-survival study, to determine the influences of gender and age, and to determine the effect of DHA-Alb in permanent middle cerebral artery occlusion (MCAo). Aim 2, focusing on hemorrhagic stroke, tests the hypothesis that DHA-Alb, and also albumin alone, attenuates brain damage in hemorrhagic stroke. We will characterize secondary neuronal injury in the perihematoma region after striatal intracerebral hemorrhage (ICH) using a multimodal approach that includes histopathology/immunochemistry and neurobehavioral methods. In anticipation of the eventual translation of albumin and DHA-Alb therapy to clinical trials in ICH patients, we will define the dose-response function and time-window and characterize swelling and blood-barrier function in the perihematoma region. This project will advance the neurotherapeutics of both ischemic and hemorrhagic stroke and, at the same time, extend our understanding of the pathophysiology of these entities. This project has very important clinical implications as DHA-Alb might permit high-grade neuroprotection to occur at substantially lower albumin doses than if native albumin itself were used - making it much safer in patients at risk of developing congestive heart failure in response to Alb therapy. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death in North America and the chief cause of chronic disability, but despite tremendous efforts in both ischemic and hemorrhagic stroke research and significant improvements in patient care within the last decade, therapy is still insufficient. The major goal of this proposal is to provide an understanding and an experimental basis for the treatment of ischemic and hemorrhagic stroke using a novel form of medical therapy that has proven to be highly promising in preliminary studies - Albumin and DHA- Albumin. With further development, this therapy may eventually prove to be beneficial in treating patients with ischemic and hemorrhagic stroke.